Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway.
Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway.
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K303R雌激素受体 - α乳腺癌突变的表达可通过成瘾对PI3K/Akt激酶途径诱导对芳香酶抑制剂的抗性。
DOI：
10.1158/0008-5472.can-08-4194
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发表时间：
2009-06-01
期刊：
影响因子：
11.2
通讯作者：
Fuqua SA
中科院分区：
文献类型：
--
作者：
Barone I;Cui Y;Herynk MH;Corona-Rodriguez A;Giordano C;Selever J;Beyer A;Andò S;Fuqua SA
芳香化酶抑制剂（AIs）正迅速成为绝经后妇女雌激素受体α (ERα)阳性乳腺癌激素治疗的首选。然而，新生和获得性耐药经常发生。我们之前已经在乳腺癌前病变和浸润性乳腺癌中发现了ERα残基303 （K303R）上赖氨酸到精氨酸的转变，这导致了雌激素过敏和对他莫昔芬治疗的抵抗。因此，我们质疑表达ERα突变的乳腺癌细胞是否会产生对AIs的耐药性。作为直接测试这种可能性的临床前模型，我们生成了用芳香酶表达载体稳定转染过表达k303r的MCF-7细胞。用芳香化酶底物雄烯二酮（AD），加或不加阿那曲唑（Ana）刺激细胞。我们发现Ana降低了ad刺激的WT细胞的生长，而表达k303r的细胞对Ana对生长的抑制作用具有抗性。我们提出耐药的机制涉及突变受体与磷脂酰肌醇-3- oh激酶（PI3K）的p85α调控亚基之间的结合增加，导致PI3K活性增加和蛋白激酶B (PKB)/Akt存活途径的激活。抑制PI3K/Akt通路的选择性“成瘾”逆转了与突变受体表达相关的AI抗性。我们的研究结果表明，K303R ERα突变可能是突变阳性乳腺肿瘤对AIs反应的新预测标志物，并且靶向PI3K/Akt通路可能是治疗激素治疗耐药肿瘤患者的有用策略。
Aromatase inhibitors (AIs) are rapidly becoming the first choice for hormonal treatment of estrogen receptor alpha (ERα)-positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ERα in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ERα mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione (AD), with or without the AI anastrozole (Ana). We found that Ana decreased AD-stimulated growth of WT cells, while K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B (PKB)/Akt survival pathways. Inhibition of the selective “addiction” to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ERα mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy.